P aediatric I nflammatory M ultisystem S yndrome T emporally related to S ARS-CoV-2 (PIMS-TS), auch bekannt als MIS-C Im Rahmen der zweiten Welle von COVID-19 sind in der Schweiz bei Kindern und Jugendlichen vermehrt Fälle von PIMS-TS aufgetreten (geschätzt ca. 50 Fälle). Über erste Fälle haben wir bereits im Frühjahr 2020 berichtet.
Nun hat ein multidisziplinäres Expertenteam unter Leitung der IG neonatale und pädiatrische Intensivmedizin (IGNPI) der Schweizerischen Gesellschaft für Intensivmedizin (SGI) nationale Empfehlungen für die Diagnostik und Therapie des PIMS-TS erarbeitet und am 30.12.2020 publiziert.
pädiatrie schweiz, im Expertenteam durch mehrere Mitglieder vertreten, unterstützt diese neuen Guidelines .
Wichtig ist das frühzeitige Erkennen eines möglichen PIMS-TS.
Die Verdachtsdiagnose in der Grundversorgung sollte gestellt werden bei :
Fieber und schlechtem Allgemeinzustand über mehrere, i.d.R. ≥ 3 Tage UND stark erhöhtem CRP (100 – >300 mg/l) UND Klinischer Symptomatik mit SARS-CoV-2 PCR bzw. Schnelltests sind mehrheitlich negativ, die Antikörper hingegen fast immer positiv. Meist liegt eine 2-6 Wochen zurückliegende, häufig asymptomatische Infektion vor.
Empfohlenes Vorgehen in der Grundversorgung :Medienmitteilung
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Version 1.0, date 30.12.2020
Best Practice Recommendations for the Diagnosis and Management of Children with Paediatric
Inflammatory Multisystem Syndrome Temporally Associated with SARS -CoV -2 (PIMS -TS ;
M ultisystem Inflammatory Syndrome in Children , MIS -C) in Switzerland
Endorsed by
the Swiss Society of Intensive Care (SGI)
the Swiss Interest Group for Pediatric and Neonatal Intensive Care (IGPNI)
the Pediatric Infectious Diseases Group Switzerland (PIGS)
the Swiss Society of Pediatrics (SGP)
Authors
Luregn J Schlapbach 1,2, MD, PhD, FCICM, Maya C Andre 3,4, MD, PhD, Serge Grazioli 5, MD, Nina
Schöbi , MD 6,7, Nicole Ritz 8, MD, Christoph Aebi 6, MD, Philipp Agyeman 6, MD, Manuela Albisetti 9,
Douggl GN Bailey 10, Christoph Berger 11, MD, Géraldine Blanchard Rohner 12, MD, DPhil, Michael
Hofer 12,13, MD, Arnauld G L’Huill ier12, MD, Mark Marston 3, MScN, Patrick M Meyer -Sauteur 11, MD,
PhD Jana Pachlopnik Schmid 14, MD, PhD, Mari e-Hel ene Perez 15, MD, Bjarte Rogdo 10, MD, Johannes
Trück 11,14, MD, D Phil , Andreas Woerner 16, MD, Petra Zimmerman 17,18, MD, PhD, Peter C
Rimensberger 5 MD, for the PIMS -TS working group of the Interest Group for Pediatric and Neonatal
Intensive Care (IGPNI) of the Swiss Society of Intensive Care and the Pediatric Infectious Diseases
Group Switzerland (PIGS)
1 Pediatric and Neonatal Intensive Care Unit, and Children`s Research Center, University Children’s
Hospital Zurich, Zurich, Switzer land
2 Child Health Research Centre, The University of Queensland, and Paediatric Intensive Care Unit,
Queensland Children`s Hospital , Brisbane, Australia
3 University of Basel Children´s Hospital, Division of Respiratory and Critical Care Medicine, Basel,
Switzerland.
4 University Children´s Hospital, Dep artment of Pediatric Hematology and Oncology, Eberhard Karls
University, Tuebingen, Germany
5 Division of Neonatal and Pediatric Intensive Care, Department of Child, Woman and, Adolescent
Medecine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
6 Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
7 Alder Hey Children’s Hospital, NHS Foundation Trust, Liverpool, United Kingdom
8 Department of Infectiology and Vaccinology , University Children’s Hospital Basel, Basel, Switz erl and
9 Department of Haematology, and Children`s Research Center, University Children’s Hospital Zurich,
Zurich , Switzerland
10 Department of Pediatric Intensive Care , Children’s Hospital St. Gallen, St. Gallen, Switzerland
11 Division of Infectious Diseases and Hospital Epidemiology , University Children’s Hospital Zurich,
Zurich, Switzerland
12 Unit of Immunology and Vaccinology, Division of General Pediatrics, Department of Pediatrics,
Gynecology and Obstetrics, Geneva University Hospitals, University of Geneva, Geneva, Switzerland
13 Pediatric Immuno -Rheumatology of Western Switzerland, Department Women -Mother -Child,
Lausanne University Hospital, Lausanne, and University Hospitals of Geneva, Geneva, Switzerland
14 Division of Immunology and Children`s Research Center, University Chi ldren’s Hospital Zurich,
Zurich, Switzerland
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15 Pediatric Intensive Care Unit , University Hospital Lausanne, Lausanne, Switzer 16 Department of
Rheumatology, University Children’s Hospital Basel, Basel, Switzerland
17 Faculty of Science and Medicine, University of Fribourg and Department of Paediatrics, Fribourg
Hospital, Fribourg, Switzerland
18 Infectious Diseases Research Group, Murdoch Children’s Research Institute, Parkville,
Australia
Corresponding author/contact :
Prof. Luregn Schlapbach, MD, PhD , FCICM
Head, Pediatric and Neonatal Intensive Care Unit
University Children’s Hospital Zurich – Eleonore Foundation
Steinwiesstrasse 75
CH -8032 Zurich Switzerland
phone +41 44 266 71 11
email: luregn.schlapbach@kispi.uzh.ch
Key words : child; COVID -19; Kawasaki disease; multisystem inflammatory syndrome; MIS -C; pediatric
multisystem inflammatory syndrome; PIMS; sepsis; septic shock
Conflict of interest statement: none declared.
Word count manuscript: 3494
Figures: 1
Tables: 3
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Abstract
Background: Following the spread of the coronavirus disease 2019 (COVID -19 ) pandemic a new
disease e ntity emerged , defined as Paediatric Inflammatory Multisystem Syndrome temporally
associated with COVID -19 (PIMS -TS), or Multisystem Inflammatory Syndrome in Children (MIS -C).
In the absence of trials, evidence for treatment remains scarce .
Purpose: To develop best practice recommendations for the diagnosis and treatment of children with
PIMS -TS in Switzerland . It is acknowledged that the field is changing rapidly, and regular revision s in
the coming months are pre -planned as evidence is increasing.
Methods : Consensus guidelines for best practice were established by a multidisciplinary group of Swiss
paediatric clinicians with expertise in intensive care, immunology/rheumatology, infectious diseases,
and haematology. Subsequent to literature review, four worki ng groups established draft
recommendations which were subsequently adapted in a modified Delphi process. Recommendations
had to reach > 80 % agreement for acceptance .
Results: The group achieved agreement on 24 recommendations, which specify diagnostic approaches
and interventions across anti -inflammatory, anti -infectious, and support therapies for children with
suspected PIMS -TS. A management algorithm was derived to guid e treatment depending on the
phenotype o f presentation, categorized into PIMS -TS with a) shoc k, b) Kawasaki -disease like and c)
undifferentiated inflammatory presentation.
Conclusion : Using available literature and guidelines from international health auth orities , the Swiss
PIMS -TS recommendations represent best practice guidelines based on currently available knowledge
to standardize treatment of children with suspected PIMS -TS in Switzerland . Given the absence of high –
grade evidence, regular updates of the recommendations will be warranted , and participation of patients
in trials should be encouraged .
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Introduction
Subsequent to the first wave of the coronavirus disease 2019 (COVID -19) pandemic 1, clusters of
children presenting with unusual multisystem inflammatory condition s emerged 2,3. The clinical
syndrome show ed some heterogeneity with patients presenting either akin to toxic shock, Kawasaki –
disease like or with undifferentiated inflammatory characteristics , in addition to evidence of current or
past COVID -19 infection in the majority of cases 4,5. Accordingly, this new disease entity has been called
Paediatric Inflammatory Multisystem Syndrome temporally associated with COV ID -19 (PIMS -TS) as
per the Royal College of Paediatrics and Child Health case definition ( RCPCH,
https://www.rcpch.ac.uk/resources/guidance -paediatric -multisystem -inflammatory -syndrome –
temporally -associated -covid -19 -pims ) and Multisystem Inflammatory Syndrome associated with
COVID -19 (MIS -C) as per the C enter for Disease Control (CDC, https://www.cdc.gov/mis -c/) and the
WHO ( World Health Organisation, https://www.who.int/publications/i/item/multisystem –
inflammatory -syndrome -in-children -and -adolescents -with -covid -19 ).
While a number of studies have attempted to explain the underlying biological and genetic mechanism s
of PIMS -TS, its pathophysiology and the observed variation in clinical presentation remains largely
unknown 6-8. It is currently assumed that a complex process involving SARS -CoV -2-specific antigen
presentation to au toreactive T cells, superantigen -like viral structures, cross -reactive SARS -CoV -2-
specific antibodies and unbalanced cytokine responses may initiate PIMS -TS in genetically predisposed
children 9-13. In other p aediatric hyperinflammatory syndromes, such as Kawasaki disease (KD) ,
macrophage activation syndrome (MAS) , and hemophagocytic lymphohistiocytosis ( HLH ), timely
initiation of anti -inflammatory therapy and immunosuppression can often reverse the hyper –
inflammatory s tate and prevent or mitigate organ damage. Therefore, therapeutic immune modulation
is widely used as a mainstay of PIMS -TS treatment with the aim to inhibit cytokine secretion and restore
immune homeostasis . In addition , PIMS -TS patients may also show signs of vasculitis , endothelial
damage , and thrombosis, hence antiplatelet and anticoagulation management in PIMS -TS represent
important additional considerations 14.
In order to standardize management in Switzerland, we aimed to develop best practice
recommendations for the diagnosis and treatment of children with PIMS -TS .
Methods
Subsequent to a call for Expressions of Interest, the Interest Group for P aediatric and Neonatal Intensive
Care (IGPNI) of the Swiss Society of Intensive Care Medicine (SSICM) and the P aediatric Infectious
Diseases Group Switzerland (PIGS) formed a working group on PIMS -TS. In total, 22 pane llists across
the fields of p aediatric intensive care, infectious diseases, immunology and rheumatology, hematology
and nursing composed the panel.
Four sub groups focus ed on the domains of i) disease criteria and diagnosis, ii) anti -inflammatory
therapies, iii) anti -infective therapies, and iv) additional support therapies including coagulation
management. Each sub group performed a focused literature review on publications since the description
of PIMS -TS in early 2020 until December 2020. In addition, we searched for available pathways ,
diagnostic and therapeutic recommendations from different international institutions 15-17. Over a period
of five weeks, weekly virtual meetings of the entire working group were held to develop and discuss
the recommendations in a modified Delphi process. Finally, vo ting was performed by the entire panel
for each recommendation using Survey Monkey . The threshold for recommendations was met if >80%
of panel lists voted for full agreement on an item .
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Statement of uncertainty:
At present, professionals remain confronted with substantial uncertainties regarding clinical
phenotypes, long -term outcomes , and optimal management 18. In the absence of randomized trials,
evidence for best treatment is minimal for the diagnostic, anti -inflammatory, anti -infectious, and
supportive measures which have be en proposed 6,19 . Recommendations therefore base primarily on
expert opinion and similar recommendations in the United Kingdom. The field is rapidly changing with
reports being published on an almost weekly basis 20, hence revision and updates of the
recommendations will be required regularly.
Recommendations
Diagnosis
1. In Switzerland, the following case definition should be used:
Adapted RCPCH – case definition 21,22
Patient aged <18 years of age. Persistent fever + inflammation (elevated CRP and neutrophils,
or lymphopaenia) + single or multi organ dysfunction (shock, cardiac, respiratory, renal,
gastrointestinal, neurological) + additional features (see Table 1 ). This may include children
fulfilling full or partial criteria for Kawasaki disease (KD).
Exclusion of any other probable cause, such as bacterial sepsis, staphylococcal/streptococcal
shock syndromes, and viral infections associated with myocarditis. Waiting f or these results
should not delay seeking expert advice.
Positive for current or recent SARS -CoV -2 infection by PCR, serology, or antigen test ; or
COVID -19 exposure within 4 weeks prior to the onset of symptoms. Waiting for these results
should not delay seeking expert advice.
2. If a child fulfils the diagnostic criteria for PIMS -TS we recommend classifying these patients
according to the presenting phenotype due to the implications for diagnostic workup and management:
Shock -like presentation : signs of shock as per the Goldstein 2005 definition of cardiovascular
failure 23 (Appendix )
Kawasaki disease -like presentation : complete or incomplete with cardiac involvement,
according to AHA 24
Undefined inflammatory presentation : persistent pyrexi a with signs of PIMS -TS but not
meeting shock criteria nor having cardiac involvement
Overall, PIMS -TS remains a rare condition and most children with SARS -CoV -2 infection will remain
asymptomatic or will exhibit only mild symptoms 4,25 . Predominant clinical features include persistent
fever and gastrointestinal symptoms, e.g. abdominal pain, vomiting or diarrhoea. Many patients may
exhibit additional clinical features ( Table 1 ). Cardiovascular impairment can be manifest at
presentation or develop during admission 26,27 . Some patients show rapid clinical deterioration often
characterized by a vasoplegic shock state requiring admission to intermediate or intensive care units
(IMC /PICU ).4,28
It is paramount to avoid anchoring bias given that PIMS -TS remains a rare condition 29, and in view of
the fact that many children suffering from other disease during the pandemic may have concomitant
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microbiological evidence of SARS -CoV -2 exposure. Other, more common differential diagnoses need
to be considered, such as, but not restricted to:
- Invasive bacterial infection
- Sepsis
- Toxic shock syndrome (TSS)
- Staph ylococcal Scalded Skin Syndro me (SSSS)
- Kawasaki disease (KD)
- Viral myocarditis/infection (EBV, CMV, adenovirus, enterovirus, HHV6)
- Serum sickness
- Acute appendicitis/acute surgical abdomen
- Gastroenteritis
- Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH)
(Appendix )
- Malignant disease s, e.g. acute leukaemia
Although the clinical presentation of PIMS -TS patients shares similarities with KD and TSS 4,25 , patients
with PIMS -TS have been reported to be older than KD patients and by definition lack microbial
confirmation of a staphylococcal or streptococcal infection.
We recommend a staged diagnostic approach, starting with standard investigations for all children
where PIMS -TS is suspected (Table 2 ), followed by more in -depth diagnostic work -up in children with
evidence of severe disease, or those with diagnostic uncer tainty. Early involvement of a paediatric
multidisciplinary team (MDT) including intensive care, immunology, infectious diseases,
rheumatology, cardiology, haematology and other s (e.g. general surgery ) should be considered .
Diagnostic measures, including laboratory tests such as markers of inflammation and organ dysfunction,
and imaging modalities such as echocardiography should be repeated sequentially depending on the
presentation , disease severity , and evolution to guide escalation and de -escalation of therapy, and to
rule out other diagnoses.
3. Patients who have been clinically well on regular wards with evidence of normal or recovering
cardiac function, and who have been afebrile (<38 degrees ) for 48 hours should be considered for
discharge home after MDT review.
In general, we suggest perform ing a follow -up visit 1 to 2 weeks and 6 weeks after discharge which
should encompass a multidisciplinary consultation. In children where cardiac involvem ent was
diagnosed, consultation of cardiology is recommended before discharge to guide frequency of follow -
up echocardiographic assessment, as cardiac function may not have fully normalized by the time of
discharge.
Anti -inflammatory therapies
4. Therapeutic immune -modulation in PIMS -TS patients requires a multi disciplinary approach.
Clinicians should re -evaluate the patient response and consider differential diagnoses at every step.
We recommend a MDT approach to guide initiation , escalation, and tapering of empiric
immunomodulatory therapy, particularly because available evidence for such treatment is currently only
based on observational reports . The panel recommends using a management algorithm ( Figure 1 ) to
guide the step -wise selection of the initial interventions. Dosing recommendations are provided in
Table 3 and were adapted from the Imperial College Healthcare NHS Trust PIMS -TS guideline (Prof.
Elizabeth Whittaker , personal communication).
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5. In patients with Kawasaki disease -like PIMS -TS, immunomodulation and management should follow
established guidelines for Kawasaki disease.
6. In patients with PIMS -TS shock, we recommend us ing immunoglobulins (IVIG, 2 g/kg) as first line
therapy.
7. In patients with PIMS -TS shock we recommend treatment with intravenous pulse high -dose
methylprednisolone (10mg/kg to max 30 mg/kg q24h for 1 -3 days, max. 1 g/day).
8. In non -shocked patients with PIMS -TS undefined inflammatory presentation clinicians sho uld
consider administration of immunoglobulins (IVIG, 2 g/kg).
9. In non -shocked patients with PIMS -TS (Kawasaki -like presentation or undefined inflammatory
presentation) clinicians should consider administration of prednisolone (2 mg/kg q24h, max. 60
mg/ day).
10. In all patients with confirmed PIMS -TS treated with steroids, steroids should be tapered over a
period of 2 -6 weeks depending on the clinical course and considering the clinical and biochemical (such
as CRP, D -Dimer and ferritin levels) response.
For children with Kawasaki disease -like PIMS -TS, the panel recommends that established institutional
or international guidelines such as the 2020 American College of Rheumatology guidelines 30 on
Kawasaki disease -like PIMS -TS should be followed. In addition, both the European SHARE initiative 31
and the American Heart Association guidelines 24 provide guidance on KD .
We recommend, based on currently available reports and in line with other recommendations, to use
intravenous immunoglobulin (IVIG) as the first line treatment in PIMS -TS patients presenting with
shock , and to consider IVIG in PIM S-TS with undefined presentation . While IVIG should be usually
administered as a single dose of 2g/kg (max. 100g/dose) , clinicians should assess the cardiac and fluid
status, particularly in patients in shock, as in some patients a slower administration become necessary .
Whi le corticosteroids have often been used as adjuncts to IVIG 32, the specific indication, dosing, timing
or type of glucocorticoid s in PIMS -TS remains unknown. The panel considered that benefit versus harm
justify pulse high -dose steroids for a duration of 1 to 3 days in PIMS -TS patients with shock , with an
initial dose of 10mg/kg methylprednisolone (max 1g/day) . Increasing the methylprednisolone dose to
30mg/kg q24h may be considered . PIMS -TS patients treated with pulse corticosteroids should receive
gastric protection with proton -pump inhibitors.
Given potential side effects and the lack of data , we advise against the use of pulse steroids in PIMS -
TS patients without shock but suggest to consider a lower dose therapy given intravenously and ,
subsequently, orally. While the optimal duration of steroid therapy in PIMS -TS remains unknown, the
joint view of the panel is that decisions on steroid treatment duration should be guided by the clinical
response (resolution of signs and symptoms), as well as by laboratory evidence of decreasing
inflammation and imp roving organ function. A longer course of steroids of up to 6 weeks may
contribute to prevent rebound inflammation.
A proportion of patients may not respond to initial treatment, and deter iorat ion of the disease can be
life -threatening. Refractory PIMS -TS is characterized by persistent fever and/ or increase of
inflammatory markers, worsening organ function, or increase in need of vasoactive drugs (measured by
Vasoactive -Inotrope Score 33) within 24 to 48 hours after start of treatment. Consideration of disease
severity in particular in PICU patients, and assessing evidence of persistent or progressive (multi -)
organ dysfunction is paramount to guide treatment escalation. Again, MDT a ssessment is recommended
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and needs to take differential diagnoses into account at every step before escalating treatment , and
should carefully evaluate risk -versus -benefit ratio of escalating immunomodulat ory therapies . For
example, PIMS -TS patients may develop secondary infection s and immuno -suppressive treatment
regimens may further impair the host defense against infection . The current list of biological drugs
includes IL -1R (i.e. anakinra) , and IL -6R (i.e. tocilizumab) and tumor necrosis factor (TNF)
(infliximab) blocking agents (Table 3). In addition , clinicians may discuss administration of a second
dose of IVIG, or pulse steroids.
11. In patients with PIMS -TS refractory to initial treatment with IVIG and steroids, and after exclusion
of alternative causes by the multidisciplinary team, we suggest consideration for anakinra. We
recommend starting at 2 -3 mg/kg q12 h s.c. (max. 100 mg/dose, total of 4 -6 mg/kg/day). In case of
clinical improvement, stopping of anakinra after 48 to 72 h ou rs should be considered in the
multidisciplinary team .
12. In patients with PIMS -TS where no clinical and biochemical improvement to anakinra treatment is
observed within 24 -48 hours, the multidisciplinary team should consider other targeted
immunomodulation therapy with either tocilizumab or infliximab.
13. Clin ical assessment and serial laboratory testing on measures of inflammation and organ
dysfunction should guide escalation and duration of immunomodulation therapy treatment.
Despite its limited licensed indication, anakinra is increasingly chosen for off -label use in PIMS -TS
patients 4,34 -36. Anakinra has been approved for subcutaneous administration, however continuo us
intravenous administration has been reported 37. Its short half -life (4 -6 hrs) ( Table 3 ), allows for repeated
re-assessment of the immun osuppressive regimen. We therefore suggest a short trial of IL -1R blockade
in PICU -hospitalized PIMS -TS patients that have not responded within a period of 24 to 36 hours
following administration of both IVIG and steroids. Anakinra dose increase in the absence of clinical
improvement may be considered in the MDT. We suggest stopping anakinra after 48 -72 hours without
taper ing in case of clinical improvement . There is no evidence to support r outine s erial cytokine level
assessment to guide cytokine -targeted therapy (CTT) .
Tocilizumab is an IL -6R blocking agent currently approved for the treatment of both systemic and
polyarticular juvenile idiopathic arthritis in children above 2 years of age. Tocilizumab has also been
used in children with PIMS -TS as IL -6 has been described to be one of the main drivers of the
inflammatory cytokine storm in this dise ase entity. However, safety concerns exist as significant side
effects have been described such as a reversible elevation of liver enzymes and an increased risk for
bacterial and fungal infections ( Table 3). Therefore, tocilizumab should be reserved for children with
life -threatening PIMS -TS in whom anakinra has failed to show a clear benefit within 48 hours. Given
the long half -life (150 hours ) tocilizumab is usually given as a single intravenous dose.
The TNF -alpha blocking agent infliximab , classically used in children with various autoimmune
inflammatory diseases has also been successfully used in children with KD. However, since infliximab
increase s the risk for secondary infections , and ba sed on its long half -life (around 8 days, Table 3 ),
infliximab should only be administered to patients with PIMS -TS who failed to respond to anakinra and
as a single intravenous dose.
Anti -infective therapies
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14. Based on the absence of evidence of remdesivir treatment for children with COVID -19 and the
proposed post -infectious concept of PIMS -TS 38 we do not recommend the routine administration of
remdesivir in PIMS -TS patients.
15. Children with suspected PIMS -TS and signs of shock or other organ dysfunction should be treated
empirically with intravenous broad -spectrum antimicrobial therapy for bacterial sepsis.
16. In children with PIMS -TS receiving intravenous antimicrobial therapy, we recommend daily
assessment (e.g., clinical, laboratory assess ment) for de -escalation of antimicrobial therapy in
consultation with infectious diseases specialists. Stopping of antimicrobial therapy should be considered
depending on the clinical course, microbiological findings, and the presence of PIMS -TS diagnostic
criteria, including evidence of recent or current SARS -CoV -2 infection by serology or PCR.
Remdesivir , a nucleoside analogue prodrug , has been approved for the treatment of COVID -19 in adults
based on emerging evidence demonstrating the efficacy in shortening time to clinical recovery 39,40 ,
however recent experience 39,41 has not confirmed these findings . The safety and effectiveness of
remdesivir for treatment of COVID -19 in children has not yet been evaluated (studies are underway)
outside case report s42,43 . Hence the role of remdesivir in the management of PIMS -TS is uncertain ,
especially as PIMS -TS represents a post -infectious disorder rather than active SARS -CoV -2 infection.
For these reasons the panel agreed that remdesivir should not be routinely used in children with PIMS -
TS. However, PIMS -TS patients may be considered for the compassiona te use of remdesivir on a case -
by -case basis 25,44 . When remdesivir is used the FDA emergency use authorization instructions for the
use of remdesivir in children >3.5 kg should be followed
(https://www.fda.gov/media/137566/download ).
Children with PIMS -TS initially often pres ent with signs and symptoms that mimic those of septic
shock and toxic shock syndrome 29 and neither clinical findings (fever, rash, abdominal symptoms),
infection marker s (CRP), nor other laboratory measures of inflammation may allow reliable
discrimination 45,46 . Mortality in children with sepsis and septic shock increase s as time to effective
antimicrobial therapy increases 47,48 . All suspected PIMS -TS patients with clinical signs of sepsis should
therefore receive prompt empiric intravenous antibiotics within one hour of pres entation for those with
shock, and within up to three hours for those without shock 49. The choice of antibiotics should be based
on local guidelines and taking into account age, epidemiology, and pre -existing medical conditions.
Antibiotics should be stream -lined or stopped on the basis of the clinical course and microbiological
culture results in discussion with t he infectious diseases team .
Supportive measures
17. All PIMS -TS patients with shoc k or other organ dysfunction must be transferred to a centre with
availability of specialized P aediatric Intensive Care Units, cardiology, infectious diseases, and
immunology/rheumatology.
18. Haemodynamic, respiratory, and other organ support should follow established guidelines such as
the Surviving Sepsis Campaign.
19. Extracorporeal Membrane Oxygenation should be considered in PIMS -TS with cardiac, respiratory,
or cardiorespiratory failure refractory to conventional management as per established guidelines
such as the Surviving Sepsis Campaign.
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Many PIMS -TS patients do not show evidence of active viral infection and may be less likely to be
infectious to healthcare workers. However, clinical staff should wear appropriate personal protective
equipment 25 as per institutional guidelines. Children should be t riaged, assessed and management in
line with recommendations for management of fever in infants <36 months, Surviving Sepsis
Campaign 47, and standard PALS resuscitation algorithms for critically ill children. As some children
progress rapidly and may develop haemodynamic compromise , close monitoring and early referral to a
tertiary centre for cardiac and PICU review is important.
20. In the absence of cont raindications, we recommend starting prophylactic i.v. unfractionated
heparin at a dose of 10 U/kg/h in PIMS -TS patients with shock. Conversion to low molecular weight
heparin (LMWH, such as enoxaparin at a dose of 0.5 mg/kg q12hrs) after the first days sh ould be
considered, depending on renal function.
21. In any other PIMS -TS patient requiring intensive care admission, we recommend prophylactic
heparin (at a dose of 10 U/kg/h) or low molecular weight heparin (LMWH, such as enoxaparin at a dose
of 0.5 mg/kg s.c. q12hrs) depending on renal function.
22. For PIMS -TS patients not requiring PICU care, individual risk factors for thrombotic
complications should be assessed to guide decisions on individualized anticoagulation therapy.
23. In patients with Kawasaki disease -like PIMS -TS, antiplatelet management should follow
established guidelines for Kawasaki disease.
24. In PIMS -TS patients not showing Kawasaki disease -like presentation , treatment with low dose
aspirin (5mg/kg daily) should be considered.
Given the increased risk of thromboembolic complication s during acute PIMS -TS 14,50 , the panel advised
to use prophylactic anticoagulation in patients of higher severity requiring PICU admission . Starting
with intravenous heparin before converting to LMWH (pending normal renal function) is suggested. In
non PICU patients, the overall ass essment of the individual risk profile should include w ell -established
risk factors such as a previous history of venous thromboembolism or a first -degree relative with venous
thromboembolism, the presence of a central line, post -pubertal age or estrogen therapy amongst other.
In addition, obesity may increase risk for thromboembolic events in patients with SARS -CoV -2
infection or PIMS -TS. At the same time, clinicians should weigh benefit of antiplatelet and
anticoagulation treatments against the i ndividual risk for clinically relevant bleeding .
Similar to classical KD patients, children with PIMS -TS irrespective of the phenotype may be at risk
for the development of coronary artery aneurysms . Hence it appears to be reasonable to consider low
dose aspirin (5mg/kg) in addition to prophylactic antic oagulation in all critically ill patients with PIMS -
TS.
Discussion
Within months of the COVID -19 pandemic spread, many countries across the globe have reported
children presenting unwell with features of severe inflammation and multisystem disease 51,52 . Using
available literatu re and guidelines from international institutions , the Swiss PIMS -TS recommendations
represent best practice guidelines based on currently available knowledge to facilitate and standardize
treatment of children with suspected PIMS -TS in Switzerland.
A number of limitations need to be considered. First, while the expert group includes specialists from
the relevant disciplines, numbers of children with PIMS -TS during the first wave of COVID -19 in
Switzerland were low , limiting experience in managing the d isease 11,34 . However, the group assessed
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institutional pathways from other health care systems and consulted world leading experts in the field
during the process. Second, the literature review performed was not systematic but focussed. Third, to
date there are no published results from randomized controlled trials in the field, and the evidence ba se
for optimal PIMS -TS management remains minimal. Finally, recommendations were issued in the
context of a well -resourced setting, where IVIG and biologicals are relatively easily available , and may
not be applicable to resource limited settings. In relat ion to applying these guidelines, c linicians should
be mindful of the risk of anchoring bias during the pandemic. Many children may test positive for
COVID -19, not necessarily implying causality . The CDC, WHO and RCPCH case definitions of PIMS -
TS bear a risk to over diagnose an assumedly rare syndrome in children who suffer from other common
infectious or inflammatory or conditions such as septic shock, or rare r conditions such as HLH.
In conclusion, i t is imperative that children with PIMS -TS are enrolled in prospective trials where
feasible 53-55, and that clinical data are collected and shared to improve our understanding of th e disease
and its best management. Given the absence of high -grade evidence 18, regular updates of the
recommendations will be required.
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Acknowledgements:
We thank Laura Chapuisat, Swiss Society of Intensive Care, for the administrative support during the
project and voting. We thank Prof. Mike Levin, and Prof. Elizabeth Whittaker, Imperial College
London, for their valuable advice.
Author contribution:
LJS and PCR designed and coordinated the work, wrote the first draft, and take responsibility for the
content of the work. MCA, NS, SG, and NR led subgroups and wrote the first draft on their section. All
other authors participated in literature review, voting, writing, and have seen and approved the final
version.
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Figure 1: PIMS -TS Diagnostic and therapeutic algorithm.
PIM S-TS Diagnostic and Treatm ent Pathw ay
Evaluation for possible PIMS-TS
Triage, Assessment and Management for evidence of sepsis/inflammation
Consider DD for PIMS-TS (case definition & table 1 & checklist)
SignsofSHOCK (ref. Goldstein 2005, appendix)
“PIMS-TS shock”
•Resuscitate as per ABC approach
•Give broad spectrum antibiotics
•IVIG 2g/kg (max 100g) single dose
•Methylprednisolone pulse 10-30mg/kg/day
IV (max 1g) for 1-3 days then 2mg/kg/day
(max 60mg) * with slow wean
•Prophylactic anticoagulation
(unfractionated heparin 10 IU/kg/h IV)
•Consider low-dose aspirin 5mg/kg/day (max
100mg) but hold if plt< 80 G/L
Multidisciplinary evaluation and consider:
•Anakinra start 2-3mg/kg/dose q12h s.c.(max 100mg/dose),
increase by 1mg/kg/dose if unresponsive
•If deterioration or no clinical improvement consider other
biologicals (Tocilizumab, Infliximab)* or second dose IVIG 2g/kg
No clinical improvement 24-36 hours after first IVIG and
methylprednisolone pulse dose (alternative causes excluded)
“Kawasaki-like PIMS-TS”
Treat per local Kawasaki
disease guideline:
•IVIG 2g/kg (max 100g)
single dose
•Aspirin (50-80mg/kg/day)
•Consider prednisolone
2mg/kg/day (max 60mg) *
in children with high risk for
IVIG resistance or >5 y old
•Consider LMWH
prophylaxis
YES NO
Multidisciplinary evaluation and
consider:
•IVIG 2g/kg (max 100g) single dose
•Prednisolone 2mg/kg/day (max
60mg)* with slow wean
•LMWH prophylaxis
•Low-dose aspirin (5mg/kg/day,
max 100mg) but hold if plt< 80
G/L
MDT: immunology, infectious diseases, respiratory medicine, rheumatology, cardiology, intensive care, general paediatrics, haematology(surgery, radiology,
neurology); consider expert opinion from another center
*Refer to the treatment Table 3for more details
No clinical improvement with persistent fever
and/or inflammation (alternative causes excluded)
Multidisciplinary evaluation and consider:
•Methylprednisolone 10-30mg/kg/day (max 1g) for
1-3 days, then 2mg/kg/day * with slow wean
•Second dose IVIG 2g/kg
•Biologicals (Anakinra, Tocilizumab, Infliximab) *
PICU with MDT support
1st & 2nd line investigations
(table 2)
1st line investigations (table 2)
Laboratory results consistent with PIMS-TS
2nd line investigations (table 2)
Features of cardiac involvement w/o shock(abnormal echo,
arrhythmias or ECG changes, elevation of cardiac enzymes,
cardiomegaly on CXR)
=> MDT and re-consider admission to IMC/PICU
“PIMS-TS undefined inflammatory
presentation”
YES NO
Alternative diagnosis ?
Sepsis
Bacterial enteritis
HLH/MAS
Other diseases
TSS
Appendicitis
Viral infection (EBV, CMV, Adenovirus,..)
KD
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Table 1. List of diagnostic criteria for PIMS -TS . Patients must be below 18 years and meet
at least one criterion for each group, including i) presence of fever, ii) organ involvement, iii)
laboratory evidence of inflammation, iv) microbiological ly proven or putative COVID -19
contact, and v) exclusion of other causes.
Clinical features
General Criteria
Required Fever O
Organ systems Single or multi -organ involvement
Gastrointestinal Abdominal pain, diarrhoea, vomiting
Abnormal liver function tests
Colitis, ileitis, ascites
O
O
O
Cardiovascular Hypotension, shock, oliguria
Myocardial dysfunction, pericardial effusion
Coronary artery dilatation
O
O
O
Respiratory Cough, sore throat
Oxygen requirement
Patchy infiltrates, pleural effusion
O
O
O
Dermatologic Conjunctivitis, periorbital swelling/redness
Mucus membrane changes
Rash
Lymphadenopathy
Swollen hands and feet
O
O
O
O
O
Neurologic Headache, confusion, irritability, reduced level of
consciousness
Syncope
O
O
Abnormal laboratory findings indicating inflammation (any combination)
Inflammatory
markers
Elevated CRP / fibrinogen / D-Dimers / ferritin,
hypoalbuminaemia, lymphopaenia, neutrophilia
O
Cardiac markers Elevated Troponin / NT -pro -BNP O
COVID -19 contact Either confirmed or putative O
Confirmed Positive for current or recent SARS -CoV -2
infection by PCR, serology, or antigen test
O
Putative COVID -19 exposure within the 4 weeks prior to
the onset of symptoms
O
No alternative plausible diagnosis (microbial or inflammatory) O
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Table 2. Recommendations for diagnostic work -up in children evaluated for PIMS -TS.
Note: where possible, PIMS -TS patients should be enrolled in observational or interventional
studies, which may include additional diagnostics.
Initial investigations in case
of suspected PIMS -TS
(according to disease severity)
Full blood count (FBC)
C-reactive protein (CRP)
Blood gas , lactate , glucose
Urea, creatinine, electrolytes (U&E)
Liver function tests (LFTs)
Coagul ation: INR, aPTT, Fibrinogen
Blood cultures (always before starting antibiotics)
Urine microscopy and culture
NPA: respiratory panel, SARS -CoV -2 PCR
Urine
Lumbar puncture if clinically indicated
Second line investigations :
(in addition to initial bloods)
Desirable measures which
should NOT delay seeking
expert opinion or treatment
Erythrocyte sedimentation rate (ESR)
Ferritin
D-dimers
Troponin
NT -pro -BNP
LDH
CK
Albumin
Triglycerides
Store serum and EDTA blood (before administration of IVIG)
EBV/CMV/Adeno -/Enterovirus blood PCR
SARS -CoV -2 serology
12 -lead ECG and echokardiography
Chest radiograph
Abdominal ultrasound (if gastrointestinal symptoms)
IL -10, IL -6, sCD25*
* consider full HLH screen if suggestive features present (e.g.
sple nomegaly, fibrinogen normal or low; ferritin >2000):
Perforin -, SAP – and XIAP -expression, NK cell degranulation and
consider HLH -directed therapy (MDT)
Follow up investigations: Unstable patient (deteriorating or in PICU):
12 -24 hourly: FBC, CRP, U&E, LFT s, coagulation, f erritin;
parameters that need to be repeated guided by clinical progress
such as Troponin and NT -pro -BNP , e cho cardiography (in
consultation with cardiology)
Stable patient with ongoing pyrexia:
24 -48 hourly: FBC, CRP U&E, LFTs, ferritin
*as above
Echocardiography 48 hourly (in consultation with cardiology)
Child improving +/ – defervescence:
48 hourly bloods or pre -discharge bloods: FBC, CRP, U&E,
LFTS
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Echocardiography before discharge
*Children with evidence of cardiac involvement sho uld be discussed with a tertiary centre for
cardiology involvement and care in PICU should be considered.
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Table 3. Anti -inflammatory therapies in patients with PIMS -TS. DISCLAIMER: Medication dosing and administration should be checked with the
local hospital pharmacists and considering recent evidence updates . W here possible, PIMS -TS patients should be enrolled in interventional
studies. Data were a cc essed from www.accessdata.fda.gov/ , www.ema.europa.eu/ , and the British Paediatric Allergy, Immunity, and Infection
Group ( Position Statement: Management of novel coronavirus (SARS -CoV -2) infection in paediatric patients in the UK and Ireland) and adapted
from the Imperial College Healthcare NHS Trust PIMS -TS guideline for external use . MDT, multidisciplinary team; IVIG, intravenous
immunoglobulins.
Class Drug Route Dose Duration Comments and side effects
Blood products IVIG IV 2 g/kg (max 100g) Infusion over
12 hours
Side effects: Aseptic meningitis, volume load, systemic inflammation,
haemolytic an aemia, neutropenia. Slower the rate or divide the dose over
two days if signs of volume overload or severe cardiac dysfunction
Corticosteroids Methylprednisolone IV
2 mg/kg daily (max 60 mg/day)
or
10-30 mg/kg daily for 1 -3 days
(max 1 g/day)
1-3 days
discuss in MDT
Side effects: Hyperglycaemia, hypertension, agitation
Prednisolone PO 1 mg/kg q12h or
2 mg/kg q24h
Up to 2 -6
weeks
Taper: over 2 -6 weeks
Biologicals Anakinra
(recombinant interleukin -1 receptor
antagonist)
SC start at 2 -3 mg/kg q12 hours
(max. 100mg/dose)
Discuss in
MDT
Escalation/taper: MDT decision. IV administration possible under different
dosing scheme.
Side effects: neutropenia, leukopenia, thrombocytopenia, eosinophilia,
headache, abdominal pain, nausea/vomiting, diarrhea, hepatitis, increased
serum transaminases, hypersensitivity reactions, injection -site reactions, skin
rash, arthralgia
Tocilizumab
(recombinant
interleukin -6 receptor
IV < 30kg: 12 mg/kg single dose
(max 800mg)
30kg: 8 mg/kg single dose
(max 800mg)
Discuss in
MDT
Escalation: If no clinical improvement after initial dose, may repeat dose 8 -
12 hours after the initial dose after MDT discussion .
Side effects: neutropenia, leukopenia, thrombocytopenia, anemia, pain,
headache, dizziness, insomnia, demyelinating disorders, ulcerations,
nausea, increased serum transaminases, liver impairment, increase in
serum lipids, pancreatitis, hypertension, hypothyroidism, hypersensitivity
reactions, Steven -Johnson -Syndrome, c onjunctivitis, nephrolithiasis,
injection -site reactions, rash
Infliximab
(chimeric tumour necrosis factor TNF
monoclonal antibody)
IV 5 mg/kg single dose Discuss in
MDT
Side effects: neutropenia, leukopenia/agranulocytosis, thrombocytopenia,
anemia, pain, headache, dizziness, insomnia, demyelinating disorders,
hypersensitivity reactions, injection -site reactions, skin rash
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Appendix:
2005 International Pediatric Sepsis Definition Consensus Conference criteria for shock
(as per Goldstein, B., et al. 2005 "International pediatric sepsis consensus conference:
definitions for sepsis and organ dysfunction in pediatrics." Pediatr Crit Care Med 2005;
6(1): 2 -8; with corrigenda in Gebara , B. M. et al. "Values for systolic blood pressure."
Pediatr Crit Care Med 2005; 6(4): 500; author reply 500 -501 ).
Presence of the following despite appropriate intravenous fluid resuscitation:
blood pressure <5th centile for age or systolic blood pressure <2 SD below normal for
age
AND/OR
need for vasoactive drugs to maintain blood pressure in normal range
AND/OR
two of the following:
- unexplained metabolic acidosis (base deficit >5.0 mEq/L)
– arterial lactate >2 times upper limit of normal
– oliguria (urine output <0.5 ml/kg/h)
- capillary refill time >5 sec
– core to peripheral temperatu re gap >3° Celsius
HLH diagnostic criteria:
(as per Pachlopnik Schmid J, Volkmer B, Ehl S: “Classification, clinical manifestation and
diagnosis of HLH”. Abla O. and Janka G. (eds.): Histiocytic Disorders. Springer Verlag ,
Stuttgart 2018; page 173 – 187. ISBN (online): 978 -3-319 -59632 -7)
The diagnosis of HLH can be established if (A) and (B) are fulfilled
A. A molecular diagnosis consistent with HLH: disease -causing mutations in PRF1 , UNC13D ,
Munc18 -2, STX11 , RAB27A, LYST, SH2D1A , or BIRC4
B. Five out of the eight criteria listed below are fulfilled:
1. Fever ≥ 38.5 °C
2. Splenomegaly (palpable below costal margin or increased size by imaging)
3. Cytopenia (affecting ≥ 2 out of the 3 lineages):
Hemoglobin (<90 g/l; in newborns, <100 g/l)
Age Group Systolic Blood Pressure (mmHg)
0 days – 1 week <5 9
1 week to 1 months <79
1 months – 1 year <7R
1 – 5 years <74
S-12 years <8P
13 - <18 years <9M
Generalsekretariat SGI IMK Institut für Medizin und Kommunikation AG, Münsterberg 1, 4001 Basel Tel. 061 / 561 53 64, E-Mail: sgi@imk.ch, www.sgi -ssmi.ch 22
Neutrophilic granulocytes (<1.0 G/l)
Platelet count (<100 G/l)
4. Hemophagocytosis (in the bone marrow or CSF)
5. Hyperferritinemia ( ≥ 500 μg/l)
6. Hypertriglyceridemia (fasting level, ≥ 3.0 mmol/l) or hypofibrinogenemia ( ≤ 1.5 g/l)
7. Elevated soluble CD25 (=soluble IL2 receptor, sIL2R) ( ≥ 2400 U/ml)
8. Decreased NK -cell cytotoxicity